The Hyperreactive Malarial Splenomegaly Syndrome in a European: Has the Treatment a Modulatory Effect on the Immune System?

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source: https://doi.org/10.7892/boris.115661 | downloaded: 1.2.2022

1ID 1990;161 (January) Correspondence 157

species (table I)'. Serum (rose bengal-positive, Wright 1:160, immunofluorescence 1:160) and CSF (rose bengal-positive, immunofluorescence 1:64) Brucellaserology were positive and the patient was treated with daily rifampin, 900 mg, plus doxycycline, 200 mg, for 8 weeks with complete recovery.

Brucellosis and tuberculosis are still endemic in our country. When the central nervous system is involved, the clinical picture and CSF analysis (elevation of protein, decreased glucose, and lymphocytic pleocytosis) may appear similar [6]. Fortunately, CSF and blood serology in neurobrucellosis are rarely negative, especially when a complete battery of tests is available, such as rose bengal and Wright agglutination, Coombs' test, and indirect immunofluorescence (as is the case in our hospital) or ELISA [7]. However, in the absence of these examinations, a correct diagnosis may be difficult [8].

Increased (>9 units/l) ADA in CSF has been reported to have a sensitivity of 1 and specificity ofO.99 in the diagnosis of tuberculous meningitis [9]. However, patients with neurobrucellosis were not included in the control groups. False-positive results have been reported in cases of purulent meningitis [9, 10], but that condition could hardly be confused with tuberculous meningitis. However, neurobrucellosis can easily be mistaken for tuberculous meningitis.

On the basis of our data, we think that physicians in countries where brucellosis and tuberculosis are endemic should take care when interpreting increased ADA in CSF, at least until neurobrucellosis can be definitively excluded.

Saraiva da Cunha, E. Gaspar, A.Meli~o-Silvestre,

R. Azevedo-Bernarda, and Carrington da Costa

Infectious Diseases Clinic, University Hospital, and General Pathology Institute, Faculty of Medicine, Coimbra, Portugal

The Hyperreactive Malarial Splenomegaly Syndrome in a European: Has the Treatment a Modulatory Effect on the Immune System?

COLLEAGUEs-The hyperreactive malarial splenomegaly (HMS) syndrome, also known as tropical splenomegaly syndrome, is believed to represent an aberrant immunologic response to repeated malarial infections and occurs in adultlong-term residents of malarious areas.

The syndrome is characterized by a gross splenomegaly with hyper- splenism, high titers of malarial IgM antibodies, a high polyclonal IgM level, hepatic and medullary lymphocytic proliferation, and normal phytohemagglutination response oflymphocytes [1]. We report a case of HMS syndrome in a white male patient once a resident of Madagascar.

A 60-year-old Swiss man had lived for 30 years in Madagascar.

He had taken antimalarial prophylaxis (chloroquine) irregularly. In

Reprints and correspondence: Dr. Daniel Betticher, Med. Klinik, Insel- spital, CH-3010 Bern, Switzerland.

The Journal of Infectious Diseases1990;161:157-159

References

1. Ogawa SK, Smith MA, Brennessel DJ, Lowy FD. Tuberculous meningitis in an urban medical center. Medicine (Baltimore) 1987;66:317-326 2. Saraiva da Cunha JG, Ma1cata L, Coelho F. Pombo V, Corte-Real R,

Pereira A, Melico-Silvestre A, Carrington da Costa R. Meningite tuberculosa do adulto: analise de 36 casos. Coimbra Medica 1988;9:237-243

3. Molavi A, LeFrock JL. Thberculous meningitis. Med Clin North Am 1985;69:315-331

4. Daniel TM. New approaches to the rapid diagnosis of tuberculous meningitis. J Infect Dis 1987;155:599-602

5. Giusti G, Galanti B. Adenosine deaminase. In: Bergmeyer HU, ed.

Methods of enzymatic analysis. 3rd ed. Vol 4. Weinheim, FRG: Ver- lag Chemie, 1984:315-323

6. Shakir RA, AI-Din ASN, Araj GF, Lulu AR, Mousa AR, Saadah MA.

Clinical categories of neurobrucellosis; a report on 19 cases. Brain 1987;110:213-223

7. Bouza E, Garcia de la Torre M, Parras F, Guerrero A,Rodnguez-Creixems M, Gobernado1. Brucellar meningitis. Rev Infect Dis 1987;9:810-822 8. Dupont B, Bletry0, Tucat G, Veyssier P, Philippon AM, Godeau P.

Neurobrucelloses chroniques avec serodiagnostic de Wright negatif.

Nouvelle Presse Med 1980;9:2721-2724

9. Ribera E, Martinez-Vazquez JM, Ocana I, Segura RM, Pascual C. Ac- tivity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults. J Infect Dis 1987;155:603-607

10. Donald PR, Malan C, van der Walt A, Schoeman JE The simultaneous determination of cerebrospinal fluid and plasma adenosine deaminase activity as a diagnostic aid in tuberculous meningitis. S Afr Med J 1986;69:505-507

1983 he gave a history of malaria which was treated by Fansidar (Roche, Basel, Switzerland). At this time the spleen was not enlarged.

At the end of 1986 the complaints were tiredness, anorexia (loss of 5 kglyear), fever, and malaise. There was no history of alcoholism or jaundice. In 1987 he returned to Switzerland; 2 months later he did not feel any improvement and therefore was hospitalized. On examination he looked pale, his weight was 73 kg, and his height 173 cm. During the hospitalization he was never febrile. The liver was not enlarged, but the spleenwastender and the lower edge reached the umbilicus. There were no stigmata of liver disease or other ab- normal physical signs.

Laboratory findings included a hemoglobin concentration of 78 gil (mean corpuscular volume, 85 fl; mean corpuscular hemoglobin, 31 pg), white blood cell count of 2.8 x 10^9/1(neutrophils 49%, lymphocytes 45 %, monocytes 3.5 %, eosinophils 1%), and throm- bocytes diminished to 113 x 10⁹/1.Erythrocyte sedimentation rate (ESR) was 130 mm/h. Plasma urea, creatinine, electrolytes, and liver function tests were all in the normal range. The proteins were 91 gil.

Electrophoresis showed raised immunoglobulins without monoclo- nal spike: serum IgG, 31 (normal, 8-18) g/I; IgA, 1.1 (0.7-4) gil;

and IgM, 14.7 (0.7-2.8) gil.

Blood smears for malarial parasites were negative several times.

No abnormalities or parasites were found in the stool or urine. Anti-

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158 Correspondence 110 1990;161 (January)

body tests for cytomegalovirus, chlamydia, Epstein-Barr virus, toxo- plasma, schistosoma, and brucella were negative. The malarial antibody titers (IF!, Tropical Institute, Basel, Switzerland) for plas- modium falciparum and vivax were1:5120. Sonography and com- puted tomography of the abdomen confirmed the splenomegaly (24 x II ern, 2400 em'). A liver biopsy showed marked sinusoi- dal infiltration with lymphocytes but no malarial pigment. Bone mar- row examination showed a hyperplasia of the erythroid cells and an excess of lymphocytes. No evidence of any malignant cells or pig- ments was seen.

Thus, the patient presented a typical picture of HMS syndrome.

No improvement could be seen during the first 2 months after his return from MadagascartoSwitzerland, so we introduced antimalarial treatment at a prophylactic dose (chloroquine, 300 mg/week). The patient soon began to feel well and had no further complaints. The spleen diminished progressively, the ESR fell almost to the normal range, and the pancytopenia disappeared (figure I).

This is the first case, to our knowledge, of a white male patient meeting the accepted criteria of HMS syndrome.It was previously not known if this illness would strike only the population of tropical countries. Different factors play an important part in the pathogenesis of this syndrome: a long period of exposure to malaria, the antimalarial drug prophylaxis [2], and a genetic or environmental predisposition [3, 4]. The association of antigens and haplotypes of HLA-DRZ was found to be more frequent in patients suffering from gross splenomegaly than in those with moderate splenic enlargement [5]. It is still not known whether a European would have the same aberrant immunologic response.

Two cases that could correspond to HMS syndrome in Europeans have been reported. The first, a Caucasian residing in Africa, showed all the criteria except the high IgM level, which was not measured [6]. The high IgM level (at least 2 SD above the local mean) allows differential diagnosis from other splenomegalies [2]. Although enlargement ofthe spleen (minimal at 10 em below the costal margin) is a major criterion of this syndrome [2], the second published case in a European [7] reported a barely palpable spleen. Those authors believed that the irregular antimalarial prophylaxis was the cause

SPLENIC VOLUME

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of the minimal enlargement. However, our case meets all the criteria of HMS syndrome.

Studies explaining the pathogenesis indicate that serum samples from patients with HMS syndrome contain lymphocytotoxic antibodies (lgM) triggered by repeated or persistent exposure to malarial parasites with specificity for1'8+suppressor lymphocytes, thus leaving relatively unopposed the stimulating effect of helper T lymphocytes on B cells [8]. The high level of B cell activity explains the production of protein in high concentrations. The treatment con- sists in the inhibition of the triggering mechanism of IgM production. Antimalarial therapy (in prophylactic dose) is usually followed by disappearance of the symptoms [2].

Asblood smears for malarial parasites were negative several times and as our patient was never febrile, we were interested to see his spontaneous course in the absence of new malarial infection in Swit- zerland. Because he felt no improvement during the first 2 months, administration of chloroquine, in an antimalarial prophylactic dose, was necessary. This treatment induced a progressive disappearance of the clinical and laboratory signs.

Chloroquine seems to have a modulatory effect on the immune system. In addition to our case, studies recently published [9] show that this drug in doses recommended for malarial prophylaxis reduces the antibody response to primary immunization with intradermal human diploid-cell rabies vaccine. These results are explained by the impaired secretion of a lymphocyte-activating factor, interleukin-l [10].However, the precise mechanism of chloroquine activity is not known, and further studies are necessary to understand the effect of this drug on the immune system in HMS syndrome.

D.C.Betticher, A. Nicole,P.Pugin, and C. Regamey Clinique Medicale, HopitalCantonal, Fribourg, Switzerland

References

1. Hewlett0,Pitchumoni CS. Tropical splenomegaly syndrome (TSS) and other diseases of the spleen. Baillieres Clin Gastroenterol 1987;1:

319-333

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Figure 1. Evolution of splenic volume, hemoglobin (Hb) concentration, and erythrocyte sedimentation rate (ESR) after administration of chloroquine.

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JID 1990;161 (January) Correspondence 159

2. Fakunle YM. Tropical splenomegaly. Part I: Tropical Africa. ClinHae- matol 1981;10:963-975

3. Greenwood BM, Groenendaal F, Bradley AK, Greenwood AM, Shen- ton F, Thlloch S, Hayes R. Ethnic differences in the prevalence of splenomegaly and malaria in The Gambia. Ann Trop Med Parasitol 1987;81:345-354

4. Crane G, Gibson D, Verrall J, Barker-Hudson P, Barker-Hudson BET, Charlwood D, Heywood P. Malaria and tropical splenomegaly syndrome in the Anga of Morobe Province. Papua New Guinea Med J 1985;28:27-34

5. Bhatia K, Crane G. HLA and tropical splenomegaly syndrome in the Upper Wattut Valley of Papua New Guinea. Hum Immunol 1985;

13:235-242

6. Lowenthal MN, Hutt MSR. Tropical splenomegaly syndrome in a Cau- casian in Africa. Br Med J 1970;3:262-263

New and Old Drugs for Treating Typhoid Fever

COLLEAGUEs-Typhoid fever continues tobea common public health problem and a significant cause of morbidity and mortality in many parts of the world. Despite the excellent in vitro activity of many antibiotic drugs against Salmonella species, the clinical efficacy of some is unclear and others are now being evaluated. Thus, the best treatment remains controversial as evidenced by several studies recently published in the Journal (1-3]. These studies demonstrated the clinical efficacy of some third-generation cephalosporins and quinolones in the treatment of typhoid fever. The authors suggested that these new drugs may be a good alternative to chloramphenicol, which is cited in all of these studies as remaining the drug of choice for treatment of typhoid fever.Althou~hmost clinicians will agree, we are uncertain that a definitive study of chloramphenicol in the treatment of typhoid fever has been carried out.

The renewed interest in the clinical efficacy of new drugs for treating typhoid is justified mainly by the potentially dangerous side effects of chloramphenicol and the data derived from studies showing that ampicillin is not as active as chloramphenicol, We recently reviewed several studies published many years ago[4-7] and observed that inadequate dosage and route of administration of ampicillin could have been responsible for these less favorable results. In fact, more recent studies have shown that intravenous ampicillin in high doses (150-200mg/kg/day) ishighlyeffectivein treating typhoid fever [8, 9].

During a recent outbreak of typhoid fever in Israel, we compared the clinical efficacy of chloramphenicol with high-dose intravenous ampicillin [10].Ourresults not only confirmed the above-mentioned data but also showed a more rapid defervescence and a lower re- lapse rate with this ampicillin regimen. We think that this less toxic

Reprints and correspondence: Dr. R. Finkelstein, Infectious Diseases Unit, Rambam Medical Center, 31096, Haifa, Israel.

The Journal of Infectious Diseases1990;161:159

0022-1899/90/6101-0042$01.00

7. Bhattacharya DN, Harries JR, Emerson PA. Tropical spleno-megaly syndrome (T.S.S.) in a European. Trans R Soc Trop Med Hyg 1983;

77:221-222

8. Piessens WF, Hoffman SL, Wadee AA, Piessens PW, Ratiwayanto S, Kurniawan L, Campbell JR, Marwoto HA, Laughlin LL. Antibody- mediated killing of suppressor T lymphocytes as a possible cause of macroglobulinemia in the tropical splenomegaly syndrome. J Clin Invest 1985;75:1821-1827

9. Pappaioanou M, Fishbein DB, Dreesen DW, Schwartz IK, Campbell GH, Sumner JW, Patchen LC, BrownWJ.Antibody response topreex- posure human diploid-eell rabies vaccine given concurrently with chloroquine. N Engl J Med 1986;314:280-284

10. Salmeron G, Lipsky PE. Immunosuppressive potential of antimalarials.

Am J Med 1983;75:19-24

drug, which has all of the advantages of chloramphenicol such as clinical efficacy and oral availability (for continuing treatment after defervescence occurs), should be considered in the treatment of typhoid fever. Certainly it is a less expensive alternative for the public health systems of developing countries.

Renato Finkelstein and Arie Markel

Infectious Diseases Unit and Department of Internal Medicine.

Rambam Medical Center, Haifa. Israel

References

I. Pape JW, Gerdes H, Oriol L, Johnson WD. Typhoid fever: successful therapy with cefoperazone. J Infect Dis 1986;153:272-276 2. Islam A, Butler T, Nath SK, Alam NH, Stoeckel K, Houser HB, Smith

AL. Randomized treatment of patients with typhoid fever by using ceftriaxone or chloramphenicol. J Infect Dis 1988;158:742-747 3. Carbon C, Weber P, Levy M, Boussougant Y, Cerf M. Short-term

ciprofloxacin therapy for typhoid fever [letter]. J Infect Dis 1987;

155:833

4. Robertson RP, Wahab MFA, RaaschFa.Evaluation of chloramphenicol and ampicillin in salmonella enteric fever. N Engl J Med 1968;

278:171-176

5. Patel KM. Ampicillin in typhoid fever. Br Med J 1964;1:1964 6. Kaye D, Rocha H, Eyckmans L, Prata A, Hook EW. Comparison of

parenteral ampicillin and parenteral chloramphenicol in the treatment of typhoid fever. Ann NY Acad Sci 1967;145:423-428

7. Snyder MJ, Gonzalez 0, Palomino C, Music SI, Hornick RB, Perroni J, Woodward WE, Gonzalez C, Dupont HL, Woodward TE. Com- parative efficacy of chloramphenicol, ampicillin and co-trimoxazole in the treatment of typhoid fever. Lancet 1976;2:1155-1157 8. Hoffman TA, Ruiz CJ, Counts GW, Sachs JM, Nitzkin JL. Waterborne

typhoid fever in Dade County, Florida. Clinical and therapeutic evaluation of 105 bacteremic patients. Am J Med 1975;59:481-487 9. Klotz SA, Jorgensen JH, Buckwold FJ, Craven Pc. Typhoid fever. An

epidemic with remarkably few clinical signs and symptoms. Arch In- tern Med 1984;144:533-537

10. Finkelstein R, Markel A, Putterman C, Lerman A, Hashman N, Merz- bach D. Waterborne typhoid fever in Haifa, Israel: clinical, microbi- ologic, and therapeutic aspects of a major outbreak. Am J Med Sci 1988;296:27-32